Nuclear PTEN Controls DNA Repair and Sensitivity to Genotoxic Stress

Bassi, C.; Ho, Jason; Srikumar, Tharan; Dowling, Ryan J.O.; Gorrini, Chiara; Miller, Sj J.; Mak, TW; Neel, B.G.; Raught, Brian; Stambolic, Vuk

doi:10.1126/science.1236188

Cited by 363 publications

(403 citation statements)

References 22 publications

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“…After exposure to genotoxic stress, SUMO-PTEN was rapidly excluded from the nucleus, and this process depended on the phosphorylation of PTEN T398 by ataxia telangiectasia mutated. 20,37 Acetylation can also regulate PTEN activity. It has been reported that PTEN is acetylated on K125 and K128 by PCAF, on K163 by HDAC6, and on K402 by CBP.…”

Section: Regulation Of Pten Functionsmentioning

confidence: 99%

“…There is no evidence proving that PTEN has a nuclear localization signal sequence and its nuclear localization may be regulated by different chemical modifications, such as phosphorylation, ubiquitylation and SUMOylation. 19,20 Within the nucleus, PTEN can act as a phosphatase or can bind with other proteins to participate in different nuclear processes. cAMP response element-binding protein (CREB), a cellular transcription factor, has been shown to be a nuclear substrate of PTEN in vivo and in vitro.…”

Section: Pten and Tumor Suppressionmentioning

confidence: 99%

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The functions of tumor suppressor PTEN in innate and adaptive immunity

Chen

Guo

2017

Cell Mol Immunol

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The tumor suppressor phosphatase and tensin homolog (PTEN) is a lipid and protein phosphatase that is able to antagonize the PI3K/AKT pathway and inhibit tumor growth. PTEN also possesses phosphatase-independent functions. Genetic alterations of PTEN may lead to the deregulation of cell proliferation, survival, differentiation, energy metabolism and cellular architecture and mobility. Although the role of PTEN in tumor suppression is extensively documented and well established, the evidence for its roles in immunity did not start to accumulate until recently. In this review, we will focus on the newly discovered functions of PTEN in the regulation of innate and adaptive immunity, including antiviral responses.

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Section: Regulation Of Pten Functionsmentioning

confidence: 99%

Section: Pten and Tumor Suppressionmentioning

confidence: 99%

The functions of tumor suppressor PTEN in innate and adaptive immunity

Chen

Guo

2017

Cell Mol Immunol

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“…Since PTEN-deficient cancer cells are hypersensitive to DNAdamaging agents, 26 we next examined the response of the reconstituted PTEN cell lines to the genotoxic agent, doxorubicin. We found that the WT PTEN cells exhibited decreased sensitivity to doxorubicin, whereas the PTEN Y336* and PTEN-HP1aKD mutants, and the empty control vector cells exhibited similar sensitivity to doxorubicin (Fig.…”

Section: C-terminal Truncated Pten Mutant Does Not Function As a Tumomentioning

confidence: 99%

Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure

et al. 2015

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The tumor suppressor, PTEN, is one of the most commonly mutated genes in cancer. Recently, PTEN has been shown to localize in the nucleus and is required to maintain genomic stability. Here, we show that nuclear PTEN, independent of its phosphatase activity, is essential for maintaining heterochromatin structure. Depletion of PTEN leads to loss of heterochromatic foci, decreased chromatin compaction, overexpression of heterochromatic genes, and reduced protein stability of heterochromatin protein 1 a. We found that the C-terminus of PTEN is required to maintain heterochromatin structure. Additionally, cancer-associated PTEN mutants lost their tumor-suppressor function when their heterochromatin structure was compromised. We propose that this novel role of PTEN accounts for its function in guarding genomic stability and suppressing tumor development.

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“…17 This function of PTEN relates to its protein but not lipid phosphatase activity and is regulated by Ataxia telangiectasia mutated, a DNA damage-induced PIKK kinase. 16 Reporting recently in this journal, Bononi and co-workers 18 showed that a fraction of PTEN localizes to the endoplasmatic reticulum (ER) and mitochondria-associated membranes.…”

mentioning

confidence: 99%

“…11 Another recently discovered mechanism of PTEN nuclear localization involves SUMOylation-mediated PTEN nuclear retention. 16 Interestingly, SUMOylated nuclear PTEN participates in the cellular response to DNA damage, helping to explain the genomic instability of PTEN-deficient tumors and their sensitivity to poly(ADP-ribose) polymerase inhibitors. 17 This function of PTEN relates to its protein but not lipid phosphatase activity and is regulated by Ataxia telangiectasia mutated, a DNA damage-induced PIKK kinase.…”

mentioning

confidence: 99%

PTEN, here, there, everywhere

Bassi

Stambolic

2013

Cell Death Differ

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Loss of function of the phosphatase and tensin homolog (PTEN) tumor suppressor is frequently found in many human malignancies. 1 PTEN antagonizes the phosphatidylinositide 3-kinase (PI3K) pathway 2 by dephosphorylating the 3 0 position of phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P 3 ] (or PIP3). 2,3 PIP3 serves as a second messenger whose levels in the plasma membrane are elevated following cell stimulation with growth factors, mediated by the activity of PI3Ks. Proteins containing pleckstrin homology (PH) domains physically interact with PIP3, bringing them into close proximity with other PH domain-containing proteins and facilitating further functional interactions that serve to propagate the membranous signal. 4 PTEN contains an N-terminal phosphatase domain that displays activity not only toward phosphatydilinositol, lipid substrates, but also toward proteinacious ones, although the search for physiologically relevant protein PTEN substrates continues. 5 The C-terminal half of PTEN features a Ca 2 þ -independent C2 domain thought to mediate PTEN interactions with the plasma membrane. 6 A cluster of cationic residues of the b-sandwich, composed of eight b-strands, on the membrane-binding face of PTEN appear to mediate membrane anchoring. 6 Recent evidence suggests further complexity of these interactions, namely, that PTEN SUMOylation at K 266 located within the CBR3 loop has a central role in PTEN membrane association, facilitating the binding of PTEN to the plasma membrane via electrostatic interactions. 7 However, structural analysis using neutron reflectometry challenges this model and demonstrates that the CBR3 loop of PTEN's C2 domain, as well as further electrostatic interactions of the phosphatase domain, is sufficient for membrane association, independent of SUMOylation. 8 PTEN unstructured C terminus, consisting of the last 50 amino acids, has also been implicated in PTEN membrane localization. Guanylate kinase with inverted orientation (MAGI) proteins, which contain PDZ domains, has been shown to bind to the PTEN C-terminal PDZ-domain interaction sequence and reinforce PTEN interaction with the plasma membrane. 9,10 In addition to membrane and cytoplasmic localization, which can be easily associated with its function in regulating the levels of 3 0 phosphorylated phosphatidylinositols, a number of reports, including several recent ones discussed below, point to specific localization of PTEN to other cellular compartments, where it may exert other tumor suppressive functions (Figure 1). For instance, PTEN is readily found in the nuclei of many cultured cells and tissues, including normal breast epithelium, proliferating endometrium, normal pancreatic islet cells, vascular smooth muscle cells, follicular thyroid cells, squamous cell carcinoma and primary cutaneous melanoma. 11 Although nuclear phosphatidylinositols have been reported, they are a part of distinct, partially detergent-resistant proteolipid complexes that are not dynamically regulated and are not likely PTEN substrates. ...

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Nuclear PTEN Controls DNA Repair and Sensitivity to Genotoxic Stress

Cited by 363 publications

References 22 publications

The functions of tumor suppressor PTEN in innate and adaptive immunity

The functions of tumor suppressor PTEN in innate and adaptive immunity

Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure

PTEN, here, there, everywhere

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